Is ANKH p.Pro5Thr (c.13C>A) pathogenic?

ANKH p.Pro5Thr (c.13C>A) is classified Pathogenic/Likely pathogenic in ANKH (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-09-17). AlphaMissense: likely benign (0.2214); Very rare (popmax 0.000254%, nfe); Associated with ANKH-related disorder.

What condition is associated with ANKH p.Pro5Thr (c.13C>A)?

ANKH p.Pro5Thr (c.13C>A) is associated with ANKH-related disorder, chondrocalcinosis 2 (ClinVar).

How common is ANKH p.Pro5Thr (c.13C>A) in the general population?

ANKH p.Pro5Thr (c.13C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ANKH p.Pro5Thr (c.13C>A)?

AlphaMissense predicts likely benign (score 0.2214) — an in-silico prediction, not a clinical call.

ANKH p.Pro5Thr

c.13C>A · rs121908410 · VCV5199

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ANKH-related disorder

Computational evidence

Protein change
AlphaMissense	0.2214	likely benign ⚠ discordant with ClinVar
REVEL	0.65	pathogenic-leaning
SaProt	LLR -7.22	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,226 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,586 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ANKH
Protein: p.Pro5Thr
Coding: c.13C>A
MANE Select: NM_054027
dbSNP: rs121908410
Type: single nucleotide variant
Location: chr5:14871435 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 5: a UniProt-annotated variant site (in ccal2)

Full ANKH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ANKH-related disorder

Also linked: chondrocalcinosis 2

Similar variants

ANKH p.Pro5Leu Likely pathogenic ★ same residue
ANKH p.Pro5Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ANKH c.*3752G>A Uncertain significance ★★ same condition
ANKH p.Ala448Thr Uncertain significance ★★ ⚠ same condition
ANKH p.Lys326Gln Uncertain significance ★★ ⚠ same condition
ANKH p.Val313Met Uncertain significance ★★ ⚠ same condition
ANKH c.1011+15T>G Benign ★★ same condition
ANKH c.1012-11T>G Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ankh-p-pro5thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown